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Showing STK35 — CLIK1 is a alias.

STK35

Serine/threonine-protein kinase 35 · UniProt Q8TDR2

Length
534 aa
Mass
58.1 kDa
Annotated
2026-06-10
12 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STK35 (CLIK1/STK35L1) is a nuclear and nucleolar serine/threonine kinase that couples cell-cycle control to actin-associated signaling and, more recently, to nutrient metabolism and genome maintenance (PMID:11973348, PMID:19756140, PMID:35021089). The full-length 534-residue protein localizes to the nucleus and nucleolus through N-terminal bipartite nuclear and nucleolar localization signals, undergoes autophosphorylation, and engages the actin cytoskeleton via two routes: recruitment to actin stress fibers by the CLP-36 PDZ-LIM adapter through CLP-36's LIM domain, and direct binding to nuclear actin through its class III PDZ-binding motif (PMID:11973348, PMID:21283756, PMID:19756140). STK35 restrains G1-to-S progression and sustains CDKN2A (p16INK4a) expression, and its depletion impairs endothelial cell migration and sprouting (PMID:21283756). Its activity is set by post-translational control: the SCP4 phosphatase forms a complex with STK35 and its paralog PDIK1L, removing inhibitory phosphorylation and stabilizing STK35, with all three acting catalytically and redundantly to support amino acid biosynthesis/transport and AML proliferation, while the NEDD4L E3 ligase ubiquitinates STK35 in a pathway placing STK35 upstream of AKT to promote glycolysis and suppress apoptosis (PMID:35021089, PMID:33117809). STK35 additionally acts as a broad regulator of the DNA damage response—depletion sensitizes cells to DNA adduct-forming agents and the kinase-domain residues A423 and W445 are functionally critical—and serves as a host kinase required for Plasmodium liver-stage infection downstream of STAT3 (PMID:34358525, PMID:42161060).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2002 Medium

    Established STK35/CLIK1 as a nuclear autophosphorylating kinase and identified a physical and spatial link to the actin cytoskeleton, answering whether this kinase has defined binding partners and a regulated localization.

    Evidence Yeast two-hybrid (36/37 clones), autophosphorylation assay, and relocalization imaging in cells

    PMID:11973348

    Open questions at the time
    • No substrate of the kinase identified
    • Functional consequence of stress-fiber recruitment not determined
    • Single-lab interaction not reciprocally validated in vivo
  2. 2009 Medium

    Corrected the gene model, defining the full-length 534-aa STK35L1 protein and confirming broad expression with nuclear/nucleolar localization, providing the correct molecular entity for subsequent study.

    Evidence Molecular cloning, SDS-PAGE, siRNA validation, and EGFP fusion imaging

    PMID:19756140

    Open questions at the time
    • Functional role of the N-terminal extension not tested
    • No catalytic characterization of full-length protein
  3. 2011 Medium

    Mapped the localization signals and a nuclear actin interaction and assigned a cell-cycle and angiogenic function, showing STK35L1 inhibits G1-to-S transition and supports endothelial migration.

    Evidence siRNA knockdown with cell-cycle analysis, expression arrays, NLS/NoLS mapping, wound-healing and Matrigel sprouting assays

    PMID:21283756

    Open questions at the time
    • Mechanism linking STK35L1 to CDKN2A expression not resolved
    • Direct kinase substrates in the cell cycle not identified
    • Whether nuclear actin binding mediates the cell-cycle effect untested
  4. 2020 Medium

    Identified NEDD4L-mediated ubiquitination of STK35 and placed STK35 upstream of AKT-driven glycolysis and apoptosis suppression, connecting the kinase to metabolic survival signaling in cancer.

    Evidence Reciprocal co-immunoprecipitation/ubiquitination assay, siRNA knockdown and overexpression with AKT phosphorylation, glycolysis, and apoptosis readouts

    PMID:33117809

    Open questions at the time
    • Whether STK35 phosphorylates an AKT-pathway component directly is unknown
    • Functional consequence of NEDD4L ubiquitination (degradation vs. signaling) not defined
    • Single-lab findings in colorectal cells only
  5. 2021 Medium

    Demonstrated an obligatory host role for STK35L1 in malaria liver-stage infection downstream of STAT3, linking the kinase to a host-pathogen cell-cycle gene program.

    Evidence siRNA knockdown with Plasmodium berghei infection assays, STAT3 phosphorylation analysis, and cell-cycle gene profiling in hepatocytes

    PMID:34358525

    Open questions at the time
    • Direct kinase target underlying infection support not identified
    • Mechanism by which STAT3 induces STK35L1 unresolved
    • Single-lab loss-of-function evidence
  6. 2022 High

    Resolved the post-translational regulation of STK35 by showing SCP4 phosphatase forms a complex with STK35 and PDIK1L, removing inhibitory phosphorylation and stabilizing it, with the kinases acting redundantly to support amino acid biosynthesis and AML proliferation.

    Evidence Domain-focused CRISPR screen, affinity purification–mass spectrometry, and gene complementation/exon-scanning assays

    PMID:35021089

    Open questions at the time
    • Phosphosites removed by SCP4 not individually mapped to function
    • Direct kinase substrates in amino acid metabolism not identified
    • Whether SCP4 regulation operates outside AML untested
  7. 2026 Medium

    Established STK35 as a broad DNA damage response regulator and pinpointed kinase-domain residues A423 and W445 as functionally critical, defining a genome-maintenance role and structure-function landmarks.

    Evidence siRNA/CRISPR depletion, saturated adenine and cytosine base-editor mutagenesis screens, and genotoxic drug sensitivity assays

    PMID:42161060

    Open questions at the time
    • DDR substrate(s) of STK35 not identified
    • Step in the DDR at which STK35 acts not defined
    • Mechanistic role of A423/W445 (catalysis vs. structure) not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct physiological substrate(s) of STK35 kinase activity remain unidentified across all its assigned roles (cell cycle, AKT signaling, amino acid metabolism, DDR, malaria infection).
  • No phosphorylation substrate experimentally established
  • Unclear whether the diverse phenotypes converge on a common molecular target
  • No structural model linking A423/W445 to substrate engagement

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0008092 cytoskeletal protein binding 2 GO:0016740 transferase activity 2
Localization
GO:0005634 nucleus 3 GO:0005730 nucleolus 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 2 R-HSA-73894 DNA Repair 1
Partners
CLP-36NEDD4LPDIK1LSCP4
Complex memberships
SCP4–STK35–PDIK1L phospho-catalytic complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 CLIK1 (STK35) is a nuclear kinase capable of autophosphorylation. Yeast two-hybrid analysis identified CLP-36 PDZ-LIM protein as a highly specific binding partner (36/37 clones). The association is mediated by the C-terminal LIM domain of CLP-36. Interaction with CLP-36 relocalizes the otherwise nuclear CLIK1 to actin stress fibers, where it disrupts the periodic staining pattern of CLP-36, establishing CLP-36 as an adapter that recruits CLIK1 to actin stress fibers. Yeast two-hybrid, autophosphorylation assay, colocalization/relocalization imaging Journal of cell science Medium 11973348
2011 STK35L1 (full-length STK35) localizes to the nucleus and nucleolus of endothelial cells via a bipartite nuclear localization signal and nucleolar localization sequences in its N-terminal region. Nuclear actin was identified as a novel binding partner mediated by a class III PDZ-binding domain motif in STK35L1. siRNA-mediated depletion of STK35L1 accelerated G1-to-S phase transition and prominently downregulated CDKN2A (p16INK4a) expression (~8.8-fold), indicating STK35L1 inhibits G1-to-S phase progression. STK35L1 depletion also impaired endothelial cell migration and sprouting. siRNA knockdown, cell cycle analysis, gene expression array, nuclear localization signal mapping, binding partner identification (PDZ-domain mediated actin interaction), wound healing assay, Matrigel sprouting assay PloS one Medium 21283756
2009 The previously published STK35 coding sequence was found to be incomplete; the full-length protein (STK35L1) is 534 amino acids (58 kDa) with a 133 amino acid N-terminal extension, and is expressed in all human cell lines tested. EGFP-STK35L1 localizes to the nucleus and nucleolus. Molecular cloning, SDS-PAGE, siRNA silencing confirmation, EGFP fusion localization imaging PloS one Medium 19756140
2022 SCP4 phosphatase forms a complex with STK35 and its paralog PDIK1L; mass spectrometry of affinity-purified complexes identified STK35 and PDIK1L as binding partners and substrates of the SCP4 phosphatase domain. SCP4 regulates STK35 through two mechanisms: (1) catalytic removal of inhibitory phosphorylation on STK35, and (2) promoting STK35 protein stability. STK35 and PDIK1L function catalytically and redundantly in the same pathway as SCP4 to maintain AML proliferation and support amino acid biosynthesis and transport. CRISPR domain-focused screen, affinity purification–mass spectrometry, gene complementation assays, CRISPR exon scanning Cell reports High 35021089
2020 NEDD4L E3 ubiquitin ligase associates with STK35 and ubiquitinates it (shown by co-immunoprecipitation). STK35 overexpression upregulates phospho-AKT, promotes glycolysis, and suppresses apoptosis in colorectal cancer cells; STK35 knockdown has the opposite effects, placing STK35 upstream of AKT signaling. Co-immunoprecipitation (ubiquitination assay), siRNA knockdown, STK35 overexpression, AKT phosphorylation assay, glycolysis measurement, apoptosis assay Frontiers in cell and developmental biology Medium 33117809
2021 STK35L1 is upregulated during Plasmodium berghei sporozoite infection in HepG2 cells and mouse liver, and this upregulation is dependent on STAT3 activation (which is phosphorylated upon infection). STK35L1 knockdown suppressed sporozoite infection and inhibited basal expression of ten cell cycle genes in infected hepatocytes (except CDKN3 and GTSE1), establishing STK35L1 as a host kinase required for the liver stage of malaria downstream of STAT3. siRNA knockdown, Plasmodium berghei infection assay, STAT3 phosphorylation analysis, cell cycle gene expression profiling Experimental cell research Medium 34358525
2026 STK35 functions as a broad regulator of the DNA damage response (DDR); its depletion sensitizes diverse human cell lines to DNA-damaging agents (especially DNA adduct-forming agents such as cisplatin and MMS). Saturated mutagenesis base-editor screening identified specific residues within the conserved kinase domain—notably A423 and W445—whose mutation markedly sensitizes cells to multiple DNA-damaging agents, indicating these residues are functionally critical. SCP4 phenocopies STK35 loss under cisplatin/MMS treatment. siRNA/CRISPR depletion, saturated adenine base editor (ABE) and cytosine base editor (CBE) screens, genotoxic drug sensitivity assays Biochemical and biophysical research communications Medium 42161060

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Clik1: a novel kinase targeted to actin stress fibers by the CLP-36 PDZ-LIM protein. Journal of cell science 61 11973348
2020 STK35 Is Ubiquitinated by NEDD4L and Promotes Glycolysis and Inhibits Apoptosis Through Regulating the AKT Signaling Pathway, Influencing Chemoresistance of Colorectal Cancer. Frontiers in cell and developmental biology 29 33117809
2011 STK35L1 associates with nuclear actin and regulates cell cycle and migration of endothelial cells. PloS one 26 21283756
2009 Identifying and characterizing a novel protein kinase STK35L1 and deciphering its orthologs and close-homologs in vertebrates. PloS one 10 19756140
2022 Promoter polymorphisms in STK35 and IFT27 genes and their associations with boar sperm freezability. Theriogenology 7 35780559
2022 SCP4-STK35/PDIK1L complex is a dual phospho-catalytic signaling dependency in acute myeloid leukemia. Cell reports 4 35021089
2021 STK35L1 regulates host cell cycle-related genes and is essential for Plasmodium infection during the liver stage of malaria. Experimental cell research 4 34358525
2018 The STK35 locus contributes to normal gametogenesis and encodes a lncRNA responsive to oxidative stress. Biology open 4 29970477
2022 STK35 Gene Therapy Attenuates Endothelial Dysfunction and Improves Cardiac Function in Diabetes. Frontiers in cardiovascular medicine 2 35097018
2026 The functional landscape of STK35 residues at single-amino-acid resolution in the DNA damage response and genotoxic drug vulnerability. Biochemical and biophysical research communications 0 42161060
2023 Retraction: STK35 gene therapy attenuates endothelial dysfunction and improves cardiac function in diabetes. Frontiers in cardiovascular medicine 0 37229227
2022 A novel bactericidal small molecule, STK-35, and its derivative, STK-66, as antibacterial agents against Gram-negative pathogenic bacteria in vitro and in vivo. Letters in applied microbiology 0 35218030

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